Stomach cancer cells make their own WNT signals to keep growing

The WNT signaling pathway is a system of proteins that cells use to communicate and control growth. It normally helps keep the stomach lining healthy, but new research published in December 2025 in Molecular Cancer shows that gastric cancer cells can turn on KRAS-driven signals, which keep growth signals active. This process allows tumors to grow on their own and reveals a weak spot that doctors may be able to target with treatment.

The lining of the stomach is constantly renewing itself, relying on carefully controlled signals that tell cells when to grow, divide and repair damage. One of the most important of these systems is the WNT signaling pathway, which acts like a communication network between stem cells and their surrounding support cells.

Under normal conditions, WNT signals help maintain healthy stomach tissue by guiding stem cells that replenish the gastric glands. When this system is disrupted, however, it can contribute to the development of cancer.

In many cancers of the colon, tumors become independent of outside WNT signals through well-known genetic mutations. Gastric cancer is different, according to researchers based within the Center for Genome Engineering, Institute for Basic Sciences in Daejeon, and the Department of Life Sciences at POSTECH in Pohang, South Korea, who conducted the study.

These common mutations are rare, leaving many unanswered questions about how stomach tumors continue to grow without normal support from their cellular environment. As researchers study how gastric tumors stop relying on WNT signals, understanding this process is critical as it could open new doors to how to slow or stop cancer growth.

Gastric cancer is a common and deadly disease in East Asia, including Korea, but it’s been studied much less on a molecular level than colorectal cancer, according to a report written by the Institute of Basic Science.

To look further into this space, mouse stomach organoids, which are tiny lab-grown versions of stomach tissue, were used. Researchers engineered these organoids to carry an activated KRAS mutation, alone or combined with other cancer-related gene changes. They also used mouse models to confirm that their findings applied in living tissue.

The team tested whether the cancer cells could grow without outside signals, removed key growth factors and used drugs to block WNT, MAPK and related pathways. They then added WNT back to see if growth could be restored. Advanced single-nucleus sequencing was also used to measure gene activity and DNA accessibility in individual cells. This helped reveal how cancer-driving signals change cell behavior.

Researchers lastly compared results from mice with organoids grown from human gastric cancer samples and analyzed large cancer cell line databases to see whether the same patterns appeared in other cancers.

The researchers discovered that healthy stomach tissue depends on WNT signals mostly from nearby support cells, not the lining itself. In mouse stomach tissue, WNT2B was identified as the main signal that keeps gastric stem cells active. Lab experiments confirmed that of the different WNT proteins tested, only WNT2B could fully replace the usual WNT supply for organoid growth.

In cancer, the system changes, according to the study. When stomach cells lost certain regulatory genes and gained an activated KRAS mutation, they no longer needed outside WNT signals. Instead, the cancer cells began making their own WNT proteins. Blocking WNT secretion stopped tumor growth unless WNT was added back, which shows that these cells relied on their own WNT production.

Further experiments showed that KRAS activates the MAPK pathway, which then turns on SMAD2/3 signaling. Combined, these pathways trigger the production of WNT7B, a powerful growth signal. This mechanism was observed not only in mice but also in human gastric cancer samples and organoids.

These findings explain how gastric tumors become self-sufficient and highlight WNT secretion as a potential treatment target.

A major strength of the study is its use of multiple approaches. For example, the team combined mouse models, lab-grown organoids, patient-derived organoids and human cancer data. They also studied cell behavior in detail and tested growth in controlled experiments, showing that KRAS-driven MAPK signaling causes WNT7B production in cancer cells.

However, there are study limitations. For instance, most experiments were done in mice or organoids, which may not fully represent tumor behavior in patients. While human data supported the findings, the study didn’t test whether blocking this pathway improves patient outcomes.

The authors suggest that drugs targeting WNT secretion or blocking the KRAS–MAPK–SMAD2/3 pathway could be effective against gastric cancer. They do recommend further research to see if WNT secretion inhibitors can be used to treat gastric cancer and other cancers with active KRAS signaling.